We have made significant progress, through support from this RO1/R37 grant, in identifying adaptations in signal transduction proteins induced in the mesolimbic dopamine system by chronic exposure to cocaine or other drugs of abuse. This neural system, which consists of dopaminergic neurons in the ventral tegmental area (VTA) and their projection regions such as the nucleus accumbens (NAc), is implicated in the reinforcing and addicting actions of these drugs. Work over the past 5 years has focused largely on two transcription factors, deltaFosB and CREB, as important mediators of the longer-lasting effects of drugs on the VTA-NAc pathway. CREB activation by drugs of abuse, which is relatively short-lived after cessation of drug use, appears to represent a mechanism of drug tolerance and dependence, and could mediate a negative emotional state seen in many addicts during early phases of drug withdrawal. The situation for deltaFosB is very different. deltaFosB, like CREB, is induced in the NAc and certain other regions by chronic exposure to drugs of abuse, however, unlike CREB, deltaFosB is long-lived in that it persists in brain for as long as 6-8 weeks after cessation of drug administration. Also unlike CREB, deltaFosB appears to mediate enhanced sensitivity to the rewarding effects of drugs of abuse. Thus, deltaFosB could represent a mechanism of relatively prolonged sensitization that contributes to features of addiction long after the last drug exposure. In formulating a plan for this competitive renewal of this R01 grant, we have decided to focus our efforts on characterizing the deltaFosB system in greater detail. (Our studies of CREB will continue with support from other grants.) Our focus on deltaFosB is justified by several considerations. First, deltaFosB is induced by virtually all drugs of abuse in the NAc and certain other regions, but there has to date been no systematic characterization of precisely where such induction occurs in brain and in which cell type. Second, deltaFosB's unusual stability provides a novel potential mechanism underlying some of the long-term effects of drugs of abuse on the brain. Yet, there has been no information available as to the biochemical mechanisms responsible for this stability. Third, virtually nothing is known about regulation of the fosB gene, the induction of which is also required for deltaFosB accumulation with drugs of abuse. Fourth, as a transcription factor, deltaFosB's interesting effects on behavior are presumably mediated via alterations in the expression of target genes, but the regulation of gene expression by deltaFosB in the NAc and other brain regions in vivo remains incompletely understood. The goal of the proposed studies, then, is to make significant progress in these several critical areas of investigation: to better understand, at the precise molecular level, exactly how and where deltaFosB is induced by chronic drug exposure, why deltaFosB persists in brain for so long, and the target genes through which deltaFosB mediates aspects of the drug-addicted phenotype. This work will contribute to our growing knowledge of drug-induced neuroadaptations in the brain at the molecular level. [unreadable] [unreadable]